Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia, which is thought to be due to an imbalance of dopamine in certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of prolonged depression and apathy similar to the negative symptoms seen in schizophrenics. Similarly, in rats the chronic administration of high doses of cocaine can produce a decrease in locomotor activity and a lack of the usual sensitization state seen with lower dose stimulant drug challenge. In the present study, we evaluated the effects of cocaine administration on the activity of tyrosine hydroxylase in five brain regions of rats. Cocaine was administered in a dose of 10 mg/kg intraperitoneally, given twice a day for 7 days. The animals were sacrificed 1 hour and 1, 3, 6, and 12 weeks after the last injection and the activity of tyrosine hydroxylase was measured in the prefrontal cortex, striatum, nucleus accumbens, substantia nigra and ventral tegmental area. Control animals consisted of rats injected on the same schedule with saline. Tyrosine hydroxylase activity was significantly increased in the cocaine-treated animals in the nucleus accumbens (11%) and nigra (14%) one hour after the last cocaine administration. A more substantial increase in tyrosine hydroxylase activity of approximately 50% occurred in the ventral tegmental area at 6 and 12 weeks after the last cocaine administration. There were no other changes in the activity of tyrosine hydroxylase at any other times in the five brain regions. These data indicate that the cell bodies of the ventral tegmental area are showing a delayed response to chronic cocaine treatment as represented by the increase in tyrosine hydroxylase activity.